Nuts are a natural source of phenolic compounds (PCs), which are characterized by their wide biological activities, particularly their role in preventing diseases associated with oxidative stress. The extraction efficacy of phenolic compounds from nuts can be significantly influenced by many factors, such as solvent composition, extraction time, extraction temperature, and solvent-to-solid ratio. In this context, the application of non-conventional techniques such as ultrasound-assisted extraction (UAE) and the use of solvents generally recognized as safe has gained growing attention for the efficient recovery of PCs. This study aimed to develop an optimized and eco-friendly method for the extraction of PCs from nuts. A multivariate experimental design was employed to evaluate key factors that influence extraction efficiency, including sample mass (0.2–0.4 g), solvent type for both defatting and extraction, pH (2–10), and extraction time (4–8 min) under UAE. An initial screening was followed by optimization using response surface methodology (RSM). The optimal conditions identified were 0.4 g of sample, 8.0 mL of hexane for defatting, 4.0 mL of methanol:water (80:20 v/v) at pH 2 for extraction, and 4 minutes of UAE. Extraction efficiency was assessed through spectrophotometric analysis of total phenolic content using the Folin–Ciocalteu method at 760 nm. The optimized protocol was applied to different nuts, walnuts, almonds, pistachios, hazelnuts, and cashews, commercially available in local markets in Mendoza, Argentina. Additionally, the antioxidant activity of the extracts was evaluated via DPPH radical scavenging assay. The results revealed notable variability in PC content and antioxidant capacity among the different nuts, suggesting that the health-promoting potential of each nuts type may differ depending on its phenolic profile.